Molecular and Coarse-Grained Modeling to Characterize and Optimize Dendrimer-Based Nanocarriers for Short Interfering RNA Delivery

Dendrimer nanocarriers are unique hyper-branched polymers with biomolecule-like properties, representing a promising prospect as a nucleic acid delivery system. The design of effective dendrimer-based gene carriers requires considering several parameters, such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity. In detail, the rational design of the dendrimer surface chemistry has been ascertained to play a crucial role on the efficiency of interaction with nucleic acids. Within this framework, advances in the field of organic chemistry have allowed us to design dendrimers with even small difference in the chemical structure of their surface terminals. In this study, we have selected two different cationic phosphorus dendrimers of generation 3 functionalized, respectively, with pyrrolidinium (DP) and morpholinium (DM) surface groups, which have demonstrated promising potential for short interfering RNA (siRNA) delivery. Despite DP and DM differing only for one atom in their chemical structure, in vitro and in vivo experiments have highlighted several differences between them in terms of siRNA complexation properties. In this context, we have employed coarse-grained molecular dynamics simulation techniques to shed light on the supramolecular characteristics of dendrimer-siRNA complexation, the so-called dendriplex formations. Our data provide important information on self-assembly dynamics driven by surface chemistry and competition mechanisms

Dispersion relations and soft pion theorems for K -> pi pi

We propose a new method to obtain the K -> pi pi amplitude from K -> pi which allows one to fully account for the effects of final state interactions. The method is based on a set of dispersion relations for the K -> pi pi amplitude in which the weak Hamiltonian carries momentum. The soft pion theorem, which relates this amplitude to the K -> pi amplitude, can be used to determine one of the two subtraction constants - the second constant is at present known only to leading order in chiral perturbation theory. We solve the dispersion relations numerically and express the result in terms of the unknown higher order corrections to this subtraction constant.Comment: Latex, 10 pages, 1 figure. Typo in eqs. (13,14) corrected, some rephrasing in the introductio

Pi-K Scattering in Full QCD with Domain-Wall Valence Quarks

We calculate the pi+ K+ scattering length in fully-dynamical lattice QCD with domain-wall valence quarks on MILC lattices with rooted staggered sea-quarks at a lattice spacing of b=0.125 fm, lattice spatial size of L =2.5 fm and at pion masses of m_pi=290, 350, 490 and 600 MeV. The lattice data, analyzed at next-to-leading order in chiral perturbation theory, allows an extraction of the full pi K scattering amplitude at threshold. Extrapolating to the physical point gives m_pi a_3/2 = -0.0574 (+- 0.0016)(+0.0024 -0.0058) and m_pi a_1/2 = 0.1725 (+- 0.0017)(+0.0023 -0.0156) for the I=3/2 and I=1/2 scattering lengths, respectively, where the first error is statistical and the second error is an estimate of the systematic due to truncation of the chiral expansion.Comment: 14 pages, 9 figure

Celiac vagus nerve stimulation recapitulates angiotensin II-induced splenic noradrenergic activation, driving egress of CD8 effector cells

Angiotensin II (AngII) is a peptide hormone that affects the cardiovascular system, not only through typical effects on the vasculature, kidneys, and heart, but also through less understood roles mediated by the brain and the immune system. Here, we address the hard-wired neural connections within the autonomic nervous system that modulate splenic immunity. Chronic AngII infusion triggers burst firing of the vagus nerve celiac efferent, an effect correlated with noradrenergic activation in the spleen and T cell egress. Bioelectronic stimulation of the celiac vagus nerve, in the absence of other challenges and independently from afferent signals to the brain, evokes the noradrenergic splenic pathway to promote release of a growth factor mediating neuroimmune crosstalk, placental growth factor (PlGF), and egress of CD8 effector T cells. Our findings also indicate that the neuroimmune interface mediated by PlGF and necessary for transducing the neural signal into an effective immune response is dependent on α-adrenergic receptor signaling

Determination of <2pi_{I=2}|Q_{7,8}|K0> in the Chiral Limit

We reconsider the dispersive evaluation of the weak matrix elements in the chiral limit. The perturbative matching is accomplished fully within the scheme dependence used in the two loop weak OPE calculations. The effects of dimension eight (and higher dimension) operators are fully accounted for. We perform a numerical determination of the weak matrix elements using our dispersive sum rules fortified by constraints from the classical chiral sum rules. A careful assessment of the attendant uncertainties is given.Comment: 18 pages, 2 figure